Encapsulation of mesenchymal stromal cells in engineered microgels for resolution of lung fibrosis

将间充质基质细胞封装在工程微凝胶中以解决肺纤维化

基本信息

批准号：
9894836
负责人：
Jae-Won Shin
金额：
$ 39.98万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9894836
关键词：
Address Alginates Antibodies Biochemical Biocompatible Materials Biomedical Engineering Biophysics Cell Therapy Cells Chronic Cicatrix Collagen Cues Data Dendritic Cells Dendritic cell activation Deposition Diagnosis Disease Disease model Encapsulated Engineering Extracellular Matrix Fibrosis Gel Genetic Glycocalyx Hydrogels Immune Impairment Inflammatory Injury Interstitial Collagenase Ligands Lung Microencapsulations Microfluidics Modeling Mus Organ Pathogenesis Pathway interactions Phenotype Production Property Pulmonary Fibrosis RGD (sequence)Research Personnel Resolution Respiratory physiology Role TNF gene TNFRSF1A gene TNFRSF1B gene Technology Testing Therapeutic Thinness Time Tissues Transplantation Tumor Necrosis Factor Activation Tumor Necrosis Factor Receptor Work base biophysical techniques collagenase curative treatments cytokine design effective therapy idiopathic pulmonary fibrosis improved in vivo knock-down member mesenchymal stromal cell multidisciplinary novel prevent programs public health relevance residence response screening stem cells

项目摘要

PROJECT SUMMARY The ability of mesenchymal stromal cells (MSCs) to adapt to their tissue niche and remodel extracellular matrix (ECM) could be therapeutically beneficial in treating fibrotic diseases. However, leveraging this property has been challenging because MSCs are rapidly cleared from tissue once delivered. Thus, specific pathways to induce MSCs to remodel the ECM and the utility of these remain unclear. We described herein a highly efficient approach to encapsulate single cells in engineered microgels with predefined biochemical and biophysical cues. We have fine-tuned this approach to show that clearance of MSCs is significantly delayed when they are delivered in thin microgels intratracheally to lungs. Importantly, our preliminary data show that this treatment decreases collagen accumulation in a murine lung fibrosis model. We show in these supporting studies amplified ability of MSCs to degrade collagen-I when the cells are encapsulated in engineered hydrogels with tunable stiffness. In this my first RO1 proposal, I will build upon these results to test the hypothesis that programming of MSCs using specifically engineered microgels activates the potential of MSCs to promote resolution of fibrosis and thus restore lung function. In Aim 1, we will determine the role of microencapsulation in controlling retention of MSCs in lungs and facilitating resolution of lung fibrosis. In Aim 2, we will determine the potentially important role of the inflammatory cytokine tumor necrosis factor-α (TNFα) in modifying the phenotype of microencapsulated MSCs to produce high amounts collagenases with enhanced potential to resolve lung fibrosis. We predict that selectively activating TNF receptor 2 in MSCs encapsulated in soft microgels can resolve lung fibrosis. The project is highly multidisciplinary in that it will employ a combination of expertise in biomaterials, lung fibrosis, biophysical, genetic, and mouse in vivo approaches to address the specific aims. The results will help to define how MSCs can facilitate resolution of fibrosis through prolonging their in vivo residence time in lungs, and modifying their phenotype through encapsulation in engineered and tunable microgels to optimize their production of collagenases. We thus hope to develop novel MSC based approaches to remodel aberrant extracellular matrix and to treat lung fibrosis. !

项目概要间充质基质细胞 (MSC) 适应其组织生态位和重塑细胞外基质的能力（ECM）可能对治疗纤维化疾病有治疗作用，但是，利用这一特性已经取得了进展。间充质干细胞一旦被输送就会从组织中迅速清除，因此，这是一个具有挑战性的问题。诱导 MSC 重塑 ECM 及其用途仍不清楚。将单细胞封装在具有预定生化和预定义的工程微凝胶中的有效方法我们对这种方法进行了微调，以表明 MSC 的清除明显延迟。重要的是，我们的初步数据表明，当它们以薄微凝胶形式通过气管内输送到肺部时。我们在这些支持中表明，这种治疗减少了小鼠肺纤维化模型中的胶原蛋白积累。当细胞被封装在工程化的细胞中时，研究增强了 MSC 降解 I 型胶原蛋白的能力在我的第一个 RO1 提案中，我将根据这些结果来测试具有可调刚度的水凝胶。假设使用专门设计的微凝胶对 MSC 进行编程可以激活 MSC 的潜力促进纤维化消退，从而恢复肺功能在目标 1 中，我们将确定其作用。微囊化控制 MSC 在肺中的滞留并促进肺纤维化的消退在目标 2 中，我们将确定炎症细胞因子肿瘤坏死因子-α (TNFα) 在改变微囊化 MSC 的表型以产生大量具有增强作用的胶原酶我们预测选择性激活 MSC 中的 TNF 受体 2 可以解决肺纤维化问题。软微凝胶可以解决肺纤维化问题，该项目是高度跨学科的，因为它将采用结合生物材料、肺纤维化、生物物理、遗传学和小鼠体内方法的专业知识研究结果将有助于确定间充质干细胞如何通过促进纤维化的解决。延长它们在肺部的体内停留时间，并通过封装来改变它们的表型因此，我们希望开发出新型的、可调节的微凝胶来优化胶原酶的生产。基于 MSC 的方法可重塑异常细胞外基质并治疗肺纤维化。！